Virtual Reality-Based Cognitive and Behavioral Therapy for Anxiety and Depression

Post by Leanna Kalinowski

A need for anxiety and depression treatment

Anxiety and depression are the most commonly diagnosed mental disorders, impacting the lives of millions of adults across the globe. While they are distinct entities, up to 60% of adults with an anxiety disorder also suffer from depressive symptoms and vice versa. Cognitive-behavioral therapy is an effective treatment for both — either alone or in combination with pharmacotherapy.  

What is Cognitive-Behavioral Therapy?

Cognitive-behavioral therapy (CBT) is a form of psychotherapy comprising a wide range of cognitive and behavioral interventions. CBT is based on the idea that behavioral changes lead to changes in emotion and cognition, and that cognitive changes lead to changes in emotion and behavior. With both strategies combined, CBT teaches patients how to identify and change their thought patterns related to the behavioral and emotional reactions that cause harm.

There are a handful of CBT techniques commonly used for people with anxiety and depression, including:

1) Psychoeducation. This is often the first step in CBT, where patients are taught how CBT works and provided the rationale for why it will be beneficial to them. Once patients learn how CBT works, they are typically able to easily apply it to their own lives in the absence of any future intervention.

2) Behavioral Activation. People with depression often withdraw from activities that previously provided natural reinforcement, leading to a cycle in which they remain inactive and do not experience the reinforcement from these activities. Behavioral activation aims to work with patients to set goals to engage in these rewarding activities (e.g., exercising or hanging out with friends) and break them out of this cycle of inactivity. 

3) Cognitive Restructuring. People with anxiety and depression often engage in negative thought patterns, including overgeneralizing and catastrophizing. Cognitive restructuring aims to help patients notice when they are engaging in these negative thought patterns and empower them with the tools needed to change these thought patterns.  

4) Exposure-based Therapy, which is especially common for people with anxiety. This therapy is based on emotional processing theory, which states that fear is represented through associative networks that maintain information about the feared stimulus (e.g., public speaking), the response to the feared stimulus (e.g., escape, avoidance, physiological responses), and the meaning of the stimulus and response (e.g., public speaking = increased heart rate = danger). In this example, exposure to public speaking in a controlled environment provides new information to indicate that public speaking isn’t that scary or dangerous, leading to a decrease in fear. 

While CBT is an effective treatment for anxiety and depression, a variety of therapy gaps exist. CBT often helps with initial treatment but is not as effective at preventing relapse of symptoms. Furthermore, CBT typically requires 10 to 20 sessions, each up to an hour-long, with guidance from a mental health professional. These gaps pose a problem for many adults, which has led to a push from mental health professionals to develop accessible ways in which CBT can be delivered, such as through smartphone apps and virtual reality technology. 

What is virtual reality technology? 

Virtual reality (VR) is a wearable technology that allows the user to feel fully immersed in a virtual world. VR commonly consists of a head-mounted display that blocks out the outside world while displaying a computer-generated, yet realistic world. This technology allows users to look around, move around, and interact with objects within the virtual world. It is often supplemented with auditory and tactile (e.g., vibrations) stimuli to mimic the real world. VR has been used in video games, military training, and business meetings is relatively affordable, and is compatible with most modern smartphones. These features make it an attractive option to enhance CBT.

How can virtual reality be used for CBT?

VR therapy is a promising avenue for implementing CBT, and Lindner and colleagues provide a comprehensive review into how some of the common approaches to CBT outlined above can be tapped into using the VR world. For example, several VR games available on the market allow users to engage in physical activity (e.g., VR boxing and tennis) and social gatherings (e.g., VR karaoke and concerts). Engaging in these activities can help patients experience the natural reinforcement required for behavioral activation therapy. 

Another example of how CBT can be adapted for a VR world is seen with virtual cognitive restructuring therapy. When this type of CBT is utilized in person, the patient must imagine an example situation to practice these cognitive restructuring techniques. However, with VR, the patient can be placed directly into these situations, without needing to imagine them, report negative thoughts by placing them into speech bubbles, and manipulate those thoughts using a virtual eraser. Engaging in these activities can help patients practice cognitive restructuring techniques in a more realistic setting.

Exposure therapy can also easily be accomplished using VR by exposing the patient to stimuli that lead to anxiety. For example, someone with a fear of spiders can undergo a VR task in which they are placed in a room with virtual spiders. Like in-person exposure therapy, this empowers the patient to change the associative networks that associate spiders with fear, leading to a decrease in anxiety. 

However, not all approaches to in-person CBT are as easily transferable to a VR context. For example, it is difficult to simulate psychoeducation using VR; evidence suggests that this method is better suited to be administered in-person or through a smartphone app that does not utilize VR. 

What’s the bottom line?

Many of the approaches to treating anxiety and depression with CBT are easily achievable using VR technology. This, coupled with its cost and accessibility, makes VR a promising avenue for enhancing CBT. Further research is needed to determine the effectiveness of VR-based CBT (1) in contrast to in-person CBT, (2) in combination with pharmacotherapy, and (3) when treating initial symptoms in addition to relapse of symptoms.

References

Ballenger. Anxiety and depression: Optimizing treatments. 2000. The Primary Care Companion to the Journal of Clinical Psychiatry. Access the publication here. 

Hundt et al. The relationship between use of CBT and depression treatment outcome: A theoretical and methodological review of the literature. 2013. Behavior Therapy. Access the publication here. 

Ioannou et al. Virtual reality and symptoms management of anxiety, depression, fatigue, and pain: A systematic review. 2020. SAGE Open Nursing. Access the publication here.

Kaczkurkin & Foa. Cognitive-behavioral therapy for anxiety disorders: An update on the empirical evidence. 2015. Dialogues in Clinical Neuroscience. Access the publication here. 

Lindner et al. How to treat depression with low-intensity virtual reality interventions: Perspectives on translating cognitive behavioral techniques into the virtual reality modality and how to make anti-depressive use of virtual reality-unique experiences. 2019. Frontiers in Psychiatry. Access the publication here.

Maples-Keller et al. The use of virtual reality technology in the treatment of anxiety and other psychiatric disorders. 2017. Harvard Reviews Psychiatry. Access the publication here. 

Roshanaei-Moghaddam et al. Relative effects of CBT and pharmacotherapy in depression versus anxiety: Is medication somewhat better for depression, and CBT somewhat better for anxiety? 2011. Depression and Anxiety. Access the publication here.

Cortisol Suppression in the Early Morning Enhances Memory Reconsolidation

Post by Andrew Vo

What's the science?

Our memories are not concrete, they are malleable and susceptible to change through a process known as reconsolidation. It has been proposed that manipulations of sleep and levels of the stress hormone cortisol can modulate reconsolidation and alter reactivated memories, however the direction of such effects is still unclear. Cortisol levels normally decrease during the evening but rise in the early morning and can also be manipulated pharmacologically. This week in The Journal of Neuroscience, Antypa et al. examine the effects of pharmacological cortisol suppression following memory reactivation on later memory retrieval.

How did they do it?

A group of healthy young adults participated in two experimental conditions (i.e., drug and placebo) spaced a minimum of 10 days apart. In each condition, participants completed (1) an encoding session, (2) a reactivation session, and (3) a retrieval session. In the encoding session, they were presented with two stories, each composed of visual slides and auditory narration. In the reactivation session that took place 2 days after encoding, participants slept in the lab from 11:00 p.m. until 3:55 a.m. when they were awakened, and one of the two encoded stories was reactivated through a cueing procedure. At 4:00 a.m., they were administered either metyrapone (a cortisol synthesis inhibitor) or a placebo before returning to bed until a 6:45 a.m. awakening. Salivary cortisol samples were collected immediately before drug intake as well as in 15-minute intervals for 3 hours after the second awakening (i.e., 6:45 a.m. to 9:45 a.m.). In the retrieval session that took place 4 days after reactivation, participants completed a multiple-choice recognition memory test on both the reactivated and non-reactivated stories. Finally, a subset of participants completed whole night polysomnography (PSG) recording for both experimental conditions.

What did they find?

Cortisol suppression via metyrapone administration just after memory reactivation enhanced performance on the multiple-choice recognition memory test in the retrieval session. This effect was not only greater for the reactivated relative to the non-reactivated story in the drug condition, but also in comparison to both reactivated and non-reactivated memories under placebo. Memory enhancement for the reactivated versus non-reactivated story negatively correlated with metyrapone-associated cortisol suppression during but not after sleep. That is, the more cortisol levels were suppressed, the more memory for the reactivated story was enhanced.

Analysis of salivary cortisol samples revealed that baseline levels (at 3:55 a.m.) did not differ between the two experimental conditions. These levels gradually lowered after awakening (6:45 to 9:45 a.m.) following metyrapone administration. Examining PSG recordings in a subset of participants, metyrapone affected subsequent sleep by increasing awake time, altering the proportion of time spent in different sleep stages, reducing total sleep time, and decreasing sleep efficiency. These metyrapone-associated changes in sleep correlated with cortisol decrease but not memory enhancement for the reactivated versus non-reactivated story because of metyrapone intake.

What's the impact?

In summary, this study demonstrated that metyrapone-mediated cortisol suppression immediately following memory reactivation enhanced reconsolidation and later recall of that memory. These findings demonstrate a cognitive (reconsolidation), physiological (sleep and cortisol levels), and pharmacological (metyrapone intake) mechanism through which episodic memories may be manipulated. Understanding of these processes holds potential clinical implications for the treatment of individuals with disease, trauma, or stress-related memory impairment.

Antypa et al. Suppressing the Morning Cortisol Rise After Memory Reactivation at 4 A.M. Enhances Episodic Memory Reconsolidation in Humans. The Journal of Neuroscience (2021). Access the original scientific publication here.

The Role of Astrocyte-Derived Cholesterol in Alzheimer’s Disease

Post by Ifrah Khanyaree

What's the science?

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of beta-amyloid (Aß) plaques in the brain and cognitive impairment. AD is estimated to affect over 20 million people worldwide. This week in PNAS, Wang and colleagues used super-resolution imaging to show that astrocyte cholesterol synthesis and its transport controls Aß accumulation and hence plaque formation in AD.                                                

How did they do it?

For the first experiment, the authors wanted to establish astrocytes as a key cholesterol source. They took a control cell culture and looked at a specific lipid cluster. They compared the size of this lipid cluster to the size of the same lipid cluster in neurons co-cultured with cholesterol-deficient astrocytes. As a second experiment, to establish the integral role of Apolipoprotein E, apoE (which is a cholesterol transport protein produced by astrocytes), they compared two cultures of cells — one loaded with apoE and a cholesterol source and the other only with apoE.

Next, the authors wanted to confirm whether astrocytes directly control Aβ peptide production (which leads to Aβ plaques). For this, only neurons were isolated from other cortical cells in one culture and, for a second mixed culture, both neurons and astrocytes were used. These cell cultures were treated with or without apoE, labelled, and then imaged with super-resolution microscopy. Finally, to confirm astrocyte-derived cholesterol as the regulator of amyloid precursor protein or APP (which generates Aß peptides) they knocked out the main transcriptional regulator of enzymes involved in cholesterol synthesis.

What did they find?

The authors found that without astrocyte derived cholesterol, the size of the lipid cluster in primary neurons was significantly smaller, suggesting that astrocytes are needed for the transport of cholesterol to neurons. This was confirmed in their second experiment, where they observed cells loaded with apoE and a cholesterol source increased in cluster diameter and those without cholesterol actually decreased in size as well as number.

They were also able to confirm the role of astrocytes in APP regulation and Aß production. The authors observed a decrease in APP and lipid cluster association in a cell culture containing only neurons and apoE. The opposite effect was seen in a mixed culture with astrocytes with neurons. There was a 2.5x increase in APP association with lipid clusters. This demonstrates that astrocytes are necessary for synthesizing the cholesterol that is then shuttled to neuronal membranes. The more cholesterol that is loaded into neuronal membranes, the more APP interacts with enzymes that cleave it to make Aß peptides. 

What's the impact?

This study found that astrocyte-derived cholesterol tightly regulates the formation of beta-amyloid plaques in AD. Before this, the role of astrocytes in AD pathogenesis was not well understood. In this study, Wang and colleagues establish a molecular pathway that defines the role of astrocytes in plaque formation by the production and distribution of cholesterol to neurons.

Wang et al. Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol. PNAS (2021). Access the original scientific publication here.